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Optogenetic-induced muscle loading leads to mechanical adaptation of the Achilles tendon enthesis in mice.

ABSTRACT: Skeletal shape depends on the transmission of contractile muscle forces from tendon to bone across the enthesis. Loss of muscle loading impairs enthesis development, yet little is known if and how the postnatal enthesis adapts to increased loading. Here, we studied adaptations in enthesis structure and function in response to increased loading, using optogenetically induced muscle contraction in young (i.e., growth) and adult (i.e., mature) mice. Daily bouts of unilateral optogenetic loading in young mice led to radial calcaneal expansion and warping. This also led to a weaker enthesis with increased collagen damage in young tendon and enthisis, with little change in adult mice. We then used RNA sequencing to identify the pathways associated with increased mechanical loading during growth. In tendon, we found enrichment of glycolysis, focal adhesion, and cell-matrix interactions. In bone, we found enrichment of inflammation and cell cycle. Together, we demonstrate the utility of optogenetic-induced muscle contraction to elicit in vivo adaptation of the enthesis.

SUBMITTER: Ganji E

PROVIDER: S-EPMC10289645 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Optogenetic-induced muscle loading leads to mechanical adaptation of the Achilles tendon enthesis in mice.

Ganji Elahe E Lamia Syeda N SN Stepanovich Matthew M Whyte Noelle N Goulet Robert W RW Abraham Adam C AC Killian Megan L ML

Science advances 20230623 25

Skeletal shape depends on the transmission of contractile muscle forces from tendon to bone across the enthesis. Loss of muscle loading impairs enthesis development, yet little is known if and how the postnatal enthesis adapts to increased loading. Here, we studied adaptations in enthesis structure and function in response to increased loading, using optogenetically induced muscle contraction in young (i.e., growth) and adult (i.e., mature) mice. Daily bouts of unilateral optogenetic loading in ...[more]

PMID: 37352350

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Project description:BackgroundAssuming that the mechanisms inducing adaptation in healthy tendons yield similar responses in tendinopathic tendons, we hypothesized that a high-loading exercise protocol that increases tendon stiffness and cross-sectional area in male healthy Achilles tendons may also induce comparable beneficial adaptations in male tendinopathic Achilles tendons in addition to improving pain and function.ObjectivesWe investigated the effectiveness of high-loading exercise in Achilles tendinopathy in terms of inducing mechanical (tendon stiffness, maximum strain), material (Young's modulus), morphological (tendon cross-sectional area (CSA)), maximum voluntary isometric plantar flexor strength (MVC) as well as clinical adaptations (Victorian Institute of Sports Assessment-Achilles (VISA-A) score and pain (numerical rating scale (NRS))) as the primary outcomes. As secondary outcomes, drop (DJ) and counter-movement jump (CMJ) height and intratendinous vascularity were assessed.MethodsWe conducted a controlled clinical trial with a 3-month intervention phase. Eligibility criteria were assessed by researchers and medical doctors. Inclusion criteria were male sex, aged between 20 and 55 years, chronic Achilles tendinopathy confirmed by a medical doctor via ultrasound-assisted assessment, and a severity level of less than 80 points on the VISA-A score. Thirty-nine patients were assigned by sequential allocation to one of three parallel arms: a high-loading intervention (training at ~ 90% of the MVC) (n = 15), eccentric exercise (according to the Alfredson protocol) as the standard therapy (n = 15) and passive therapy (n = 14). Parameters were assessed pre- and-post-intervention. Data analysis was blinded.ResultsPrimary outcomes: Plantar flexor MVC, tendon stiffness, mean CSA and maximum tendon strain improved only in the high-loading intervention group by 7.2 ± 9.9% (p = 0.045), 20.1 ± 20.5% (p = 0.049), 8.98 ± 5.8% (p < 0.001) and -12.4 ± 10.3% (p = 0.001), respectively. Stiffness decreased in the passive therapy group (-7.7 ± 21.2%; p = 0.042). There was no change in Young's modulus in either group (p > 0.05). The VISA-A score increased in all groups on average by 19.8 ± 15.3 points (p < 0.001), while pain (NRS) dropped by -0.55 ± 0.9 points (p < 0.001).Secondary outcomesCMJ height decreased for all groups (-0.63 ± 4.07 cm; p = 0.005). There was no change in DJ height and vascularity (p > 0.05) in either group.ConclusionDespite an overall clinical improvement, it was exclusively the high-loading intervention that induced significant mechanical and morphological adaptations of the plantar flexor muscle-tendon unit. This might contribute to protecting the tendon from strain-induced injury. Thus, we recommend the high-loading intervention as an effective (alternative) therapeutic protocol in Achilles tendinopathy rehabilitation management in males.Clinical trials registration numberNCT02732782.

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Optogenetic-induced muscle loading leads to mechanical adaptation of the Achilles tendon enthesis in mice.

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Optogenetic-induced muscle loading leads to mechanical adaptation of the Achilles tendon enthesis in mice.

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